RESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Aß). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC50 values of 6.34µM and 0.30µM, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex™ Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.
Asunto(s)
3-Hidroxiacil-CoA Deshidrogenasas/antagonistas & inhibidores , Enfermedad de Alzheimer/tratamiento farmacológico , Benzotiazoles/farmacología , Inhibidores Enzimáticos/farmacología , Monoaminooxidasa/metabolismo , Compuestos de Fenilurea/farmacología , Tiourea/farmacología , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , Enfermedad de Alzheimer/metabolismo , Benzotiazoles/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Compuestos de Fenilurea/química , Relación Estructura-Actividad , Tiourea/síntesis química , Tiourea/químicaRESUMEN
Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9 b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50 : 1.5â µm), butyrylcholinesterase (BChE IC50 : 2.4â µm) and MAOâ A (IC50 : 0.49â µm), and it is also a weak inhibitor of MAOâ B (IC50 : 53.9â µm). Although its cytotoxic (IC50 : 5.5±0.4â µm) and hepatotoxic (IC50 : 1.22±0.11â µm) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63±4 and 11.50±0.77â µm, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.